The majority of breast cancers occur in postmenopausal women with 75% of these tumors being estrogen dependent as defined by estrogen receptor (ER) a positivity (1). Tamoxifen, an anti-estrogen, has been the mainstay of treatment for hormone-dependent breast cancers. However, recent clinical trials have shown that inhibitors of aromatase, which catalyzes the rate-limiting step of estrogen biosynthesis, may be more effective than tamoxifen in treating hormone-dependent breast cancers in postmenopausal women (2). Unfortunately, resistance to both these endocrine therapies is inevitable in metastatic breast cancer (3). Thus, there is a compelling need to develop more effective therapies for breast cancer patients with acquired anti-estrogen resistance in addition to those with intrinsic resistance to anti-estrogen and anti-HER2 therapies.
Genomic instability, including chromosomal abnormalities, is a characteristic of both hereditary and sporadic breast cancers (4). The tumors in inherited breast cancer that result from loss of either BRCA1 or BRCA2 function have a defect in the recombinational repair of replication-associated double-strand break (DSB) (5). This specific DNA repair defect in BRCA tumors not only underlies the numerous chromosomal rearrangements in these cells but also results in their hypersensitivity to inhibitors of poly(ADP-ribose) polymerases (PARP) that generate replication-associated DSBs by inhibiting the repair of DNA single-strand breaks (SSB; refs. 4, 6). On the basis of these preclinical studies, potent and specific inhibitors of PARP were developed and are currently being evaluated in clinical trials as therapeutic agents for inherited forms of breast and ovarian cancer (7, 8).
The promising initial results with PARP inhibitors have stimulated interest in DNA repair proteins as therapeutics targets and the characterization of DNA repair defects in sporadic cancers. Recent studies have begun to characterize an alternative (ALT) nonhomologous end joining (NHEJ) pathway that repairs DSBs and is much more error prone than the major DNA-PK-dependent NHEJ pathway (9). Although ALT NHEJ is a relatively minor pathway in normal cells, there is emerging evidence that this pathway is upregulated, whereas the DNA-PK-dependent pathway is downregulated in a significant fraction of cancers (10-12). While genomic instability generated by ALT NHEJ may drive disease progression, ALT NHEJ appears to function as a cancer cell-specific therapeutic target because cells with increased ALT NHEJ are more dependent upon this pathway for survival and are more sensitive to inhibitors that target the ALT NHEJ pathway.
A significant fraction of cell lines established from leukemias and solid tumors have elevated levels of ALT NHEJ proteins and ALT NHEJ activity. These include cell lines from chronic and acute myeloid leukemias and from breast, head and neck, lung and colon cancers, and in clinical samples from patients with chronic myeloid leukemia and breast cancer. Notably, ALT NHEJ activity is elevated in forms of breast cancer and leukemia that are resistant to frontline therapies and these cells are hypersensitive to combination of PARP and DNA ligase inhibitors. Together these studies suggest that a significant fraction of patients will be candidates for treatment with therapies that target ALT NHEJ. This will include patients with disease that is resistant to effective frontline therapies, such as anti-estrogens in breast cancer and patients with disease for which there is no effective therapy, such as pancreatic adenocarcinoma and small cell lung cancer. In the absence of a targeted therapy, patients with these diseases are often treated with combinations of cytotoxic chemotherapeutics that have severe side-effects. For example, (Lowery, et al., “Genomics and pharmacogenomics of pancreatic adenocarcinoma”, Pharmacogenomics, 2012 February; 12(1):1-9) the combination of several cytotoxic agents; infusional 5-FU, irinotecan and oxaliplatin, known as FOLFIRINOX, has improved survival in patients with an excellent functional status and stage IV disease by 4.3 months compared with gemcitabine alone but did result in a significant increase in toxicities, in particular gastrointestinal and hematologic. Cancers such as pancreatic cancer and small cell lung cancer without a targeted and/or effective therapy were the subject of the Recalcitrant Cancer Act that was recently passed by Congress. Given the therapeutic and toxicity limitations of existing treatments, there is a need for therapies that are effective in treating patients who suffer from pancreatic cancer (including, but not limited to, pancreatic adenocarcinoma, islet cell carcinoma, and neuroendocrine tumors) and other cancers for which there is no targeted and/or effective therapy.